THYROID ORIGINAL STUDIES

Volume 30, Number 12, 2020

Mary Ann Liebert, Inc. THYROID FUNCTION AND DYSFUNCTION
DOI: 10.1089/thy.2019.0535

Clinical Parameters Are More Likely to Be Associated

with Thyroid Hormone Levels than with Thyrotropin Levels:
A Systematic Review and Meta-Analysis

Stephen P. Fitzgerald,1–3 Nigel G. Bean,4,5 Henrik Falhammar,6–8 and Jono Tuke4,5

Background: Though the functional states of other endocrine systems are not defined on the basis of levels of
controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone thy-
rotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine
(fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference
ranges, provide the better guide to the range of clinical parameters associated with thyroid status.
Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of
thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was per-
formed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia,
frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for
quality by using a modified Newcastle–Ottawa score. Preferred Reporting Items for Systematic Reviews and
Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the
relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters.
Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were
associated with thyroid hormone levels significantly more often than with TSH levels—the converse was not
true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly
associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels
were 53% and 23% ( p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were
comparably associated with clinical parameters ( p = 0.71). More sophisticated statistical analyses, however,
indicated that the associations with TT3/fT3 were not as robust as the associations with fT4.
Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical
parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong
negative population correlation between thyroid hormones and TSH. Clinical and research components of thyr-
oidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration.

Keywords: thyroid hormones, TSH, clinical parameters, correlation, subclinical thyroid dysfunction

Introduction ism (normal TSH and thyroid hormone levels), overt thyroid
dysfunction (abnormal TSH and thyroid hormone levels),

T hyroid function testing (1,2) and monitoring

(3) are based on the measurement of thyrotropin (TSH)
levels. Patients are therefore classified as having euthyroid-
subclinical thyroid dysfunction (abnormal TSH/normal thy-
roid hormone levels), and isolated hyper/hypothyroxinemia
(normal TSH/abnormal thyroid hormone levels).

Departments of 1General Medicine and 2Endocrinology, Royal Adelaide Hospital, Adelaide, South Australia.
3
School of Medicine, University of Adelaide, Adelaide, South Australia.
4
School of Mathematical Sciences, University of Adelaide, Adelaide, South Australia.
5
ARC Centre of Excellence for Mathematical and Statistical Frontiers, University of Adelaide, Adelaide, South Australia.
6
Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.
7
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
8
Wellbeing and Chronic Preventable Diseases Division, Menzies School of Health Research and Royal Darwin Hospital, Tiwi, Australia.
ª Stephen P. Fitzgerald et al., 2020; Published by Mary Ann Liebert, Inc. This Open Access article is distributed under the terms of the
Creative Commons License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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1696
This classification of thyroid function is based on the
concept of TSH levels being the most sensitive indicator of
thyroid function such that subclinical thyroid dysfunc-
tion as currently defined is believed to be more signifi-
cant than isolated hyper/hypothyroxinemia (2), as indicated
by the alternative term for the latter, ‘‘euthyroid hyper/
hypothyroidism’’ (4).
Subclinical thyroid dysfunction is common and comprises
most cases of thyroid dysfunction with a population preva-
lence of *5% (5–9), increasing to 15% in older adults (9).
Even though it is generally asymptomatic or associated only
with non-specific symptoms, subclinical thyroid dysfunction
has been associated with many adverse outcomes across a
variety of organ systems (5–9). Therefore, despite the lack of
convincing evidence of significant benefit (10,11), treatment
for subclinical thyroid dysfunction has been recommended in
certain circumstances (6–9).
It has previously been suggested by some authors that the
earlier definition of subclinical thyroid dysfunction is overly
simple and that its diagnosis should not be based solely on
the TSH level being outside of a general population range
(12,13). Rather, it is claimed that more accuracy may be
achieved by defining a normal reference range for the com-
bination of thyroid hormones and TSH.
However, any model whereby judgment of the thyroid
status includes consideration of the TSH level is anomalous,
in that the levels of other physiological parameters are not
judged by the levels of their controlling hormones. For ex-
ample, whether or not an individual has hypoglycemia or
hypercalcemia is not determined by reference to insulin (14)
or parathyroid hormone levels (15), respectively. Adreno-
corticotropic hormone (ACTH) levels, though helpful in di-
agnosing adrenal autonomy, are not considered diagnostic for
Cushing’s syndrome (16). In general, the level of a control-
ling hormone is used to determine the cause of a disturbance
rather than identifying whether or not there is a disturbance
(14–16).
We, therefore, aimed at determining whether or not a
systematic review of the literature might indicate the relative
merits of thyroid hormone levels and TSH levels, in terms
of associations with a broad range of clinical parameters.
Because of the strong negative population correlation be-
tween free thyroxine (fT4) and TSH (17,18), we expected to
find associations between both TSH and fT4 levels and the
clinical features of thyroid dysfunction. We further reasoned
that if the clinical features were associated better with TSH
levels, the current rationale for thyroid function testing and
the current consequent clinical and research classifications
and practices would be supported, but, if the clinical features
were associated better with thyroid hormone levels, these
classifications and practices would warrant review. In this
latter circumstance, the previously noted associations of
clinical features with TSH levels could be attributed to the
aforementioned strong negative population correlation be-
tween fT4 and TSH.
Methods
Search strategy
Up to October 9, 2019, a systematic search was performed
of PubMed/MEDLINE by using the following terms: thy-
roxine (T4), fT4, total triiodothyronine (TT3), free triiodo-
FITZGERALD ET AL.
thyronine (fT3), TSH, and subclinical. No restrictions were
placed on language, country, or publication date. The re-
sulting literature was first examined to confirm the previously
reported general trends of association between clinical
parameters and thyroid status.
On account of the results of this first examination of the
literature (see Results section), we studied atrial fibrillation
(AF) and other cardiac parameters, bone density and fracture,
cancer, death, frailty, dementia and associated pathology,
obesity, features of the metabolic syndrome, and pregnancy
outcomes. We specifically sought studies that addressed the
associations between both TSH and thyroid hormone levels,
determined simultaneously in the same individuals, with any
of the clinical parameters just mentioned.
Study selection and data extraction
Initially, the titles of the articles were screened for rele-
vance and then the abstracts, with full-text reports of po-
tentially relevant reports were reviewed. Additional relevant
articles were searched for in the reference lists of the re-
trieved full-text studies. If repeated study was made of the
same cohort, only the latest was included. The literature
search data extraction, identification of additional relevant
articles, and critical appraisal were conducted independently
by two of the authors (S.P.F. and H.F.), and any discrepancies
were resolved by consensus with reference to the criteria
described in the next section. Should consensus regarding
any article not have been achieved, the default position was
that the article would be included. No study that contradicted
the results of our work was knowingly excluded.
Studies reporting on associations of levels of fT4, TT3/
fT3, and TSH with clinical features related to thyroid dys-
function were included. We included both TT3 and fT3, as
there were relatively few studies of fT3. We also included
analyses comparing associations with subclinical hypothy-
roidism and euthyroid hypothyroxinemia, reasoning that this
is a comparison of low thyroid function defined on the basis
of TSH levels or thyroid hormone levels, respectively. Re-
ports were excluded if the studied population was <100 in-
dividuals. Review articles, editorials, meta-analyses, and
meeting abstracts were also excluded.
The following information was extracted from each such
study: first author, country, number of individuals, sex, age
intervals, nature of the study, and the relevant clinical param-
eter. As there were many subtle different parameters examined,
we also grouped the parameters into eight major phenotypes or
systems: ‘‘cardiac,’’ bone,’’ ‘‘dementia,’’ ‘‘cancer,’’ ‘‘mortali-
ty,’’ ‘‘frailty,’’ ‘‘metabolic,’’ and ‘‘pregnancy.’’ We recorded
any associations with thyroid hormones and/or TSH, in addition
to the statistical techniques and degrees of significance of any
associations ( p-values and/or confidence limits). We also re-
corded the presence of ‘‘incongruent’’ associations, that is,
associations in the opposite direction to that normally expected
(e.g., obesity having associations with high thyroid function), or
associations of thyroid hormones in the same direction as as-
sociations with TSH, as indicators of reverse causation (Sup-
plementary Table S1) (19).
As our study was not directed at a collection of works
addressing therapeutic outcomes of an intervention, the use
of a quality assessment (the Newcastle–Ottawa scale) was
adjusted to suit this setting. Principally, this adjustment
ASSOCIATION OF THYROID TESTS AND CLINICAL STATES
consisted of allowing for continuous, as well as binary
quantifications, of clinical outcomes and exposure to thyroid
hormone levels. Articles were scored according to the rep-
resentativeness of the subjects, the similarity of the sub-
jects apart from differences in the parameter of interest, the
reliability of the classification of thyroid status and parameter
status, control for confounding factors, and for prospective
studies, the demonstration that outcome was not present at
study onset, the adequacy of length and completeness of
follow-up. The Preferred Reporting Items for Systematic
Reviews and Meta-analyses guidelines were followed (20).
Statistical analysis
To determine whether thyroid hormone levels or TSH
levels were associated better with the examined clinical
parameters, we analyzed the earlier studies as to the relative
frequencies of significant associations of thyroid hormone
and TSH levels with the clinical parameters. We then per-
formed further analyses to confirm that these findings did not
result from any systematic bias.
We classified each result in a study as showing a significant
result or a non-significant result. By a significant result, we
mean that a given thyroid test has been shown to be associ-
ated with a given condition at a 5% significance level. We
treated the result as a binary response variable with the levels
of success (significant) and failure (non-significant). We
combined TT3 and fT3 as TT3/fT3.
The predictors considered were the type of thyroid test (i.e.,
TSH, fT4, or TT3/fT3), the clinical system under consideration;
the number of subjects in the analysis; and the number of cov-
ariates in the model. To account for the repeated analysis within
each study, we also incorporated a random intercept term. We
considered random intercepts for the study, the cohorts nested
within each study, the type of analysis nested within the study,
and the complexity of the models nested within the studies.
Pairwise comparisons of the thyroid tests were performed
at a 5% overall significance level for those models where a
significant effect of the predictor, type of thyroid test, was
found. We calculated the Tukey pairwise comparisons be-
tween the thyroid tests by using the multcomp package (21).
We conducted a McNemar analysis on the contingency ta-
bles for each comparative pair of thyroid tests. We tested the
null hypothesis that there was no change in the proportion of
significant results between the two thyroid tests under con-
sideration. As a final attempt to account for dependency
within each study, we performed a simple logistic regression
analysis by using only a single randomly chosen analysis
from the series of nested models in each study. We performed
this for each of the following strata:

smallest number of subjects, simple model;

smallest number of subjects, complex model;

largest number of subjects, simple model; and

largest number of subjects, complex model.
We performed a sensitivity study minimizing the contri-
bution of possible reverse causation, analyzing only the pro-
spective analyses from studies that were free of incongruent
associations.
All modeling was performed by using the lme4 (22) and
lmerTest (23) packages in R (24), and all codes are available
at https://github.com/jonotuke/TSH_2019.
1697
Results
We found, in our first examination of the literature, that
though the findings were not unanimous, there was general
consistency of the data. In general, consistent with prior work (8),
AF (25–31), osteoporosis (32–39), and cancer (40–43) were
associated with higher thyroid function that was defined by using
TSH and/or thyroid hormone levels, across and beyond the ref-
erence range, and steatohepatitis (44–46) and other features of
the metabolic syndrome (19,47–66) were associated with lower
thyroid function. Both high and low thyroid function, as com-
pared with mid-range thyroid function, were associated with
clinical and pathological features of cognitive decline (26,67–
75), frailty (76–79), total/cardiovascular mortality (26,80–88),
cardiac physiology (89), cardiac disease (apart from AF)
(26,31,67,83–85,88,90,91), and pregnancy outcomes (92–99).
There were many series finding these associations in the
context of subclinical thyroid dysfunction. Many of these
studies (25,50,51,67,83–85,87–89), however, did not address
the relative associations of clinical parameters with TSH and
thyroid hormone levels, the focus of our study.
In the end, we identified 58 studies that addressed this
question (Fig. 1; Table 1). We found no previous synthesis
of the data on the effect of thyroid function, as measured by
TSH in comparison to thyroid hormone levels, across a range
of organ systems. One meta-analysis restricted to AF (27) was
not included in our analysis. Many of the studies addressed
multiple parameters summarized by those indicated in Table 1.
We found 22 studies (19,26,30,31,34,35,39,41,44,45,48,
55,60–62,65,66,71,75,78,79,91) that examined associations
with fT4, TT3/fT3, and TSH and a further 36 studies
(26,29,33,36–38,40,42,43,45,47,49,52–54,56,63,64,69,73,74,
76,77,80–82,86,90,92–99) that examined associations with
only fT4 and TSH levels.
These 58 studies included cross-sectional and prospective
cohort studies, diverse populations, and both sexes. They
were contemporary and of high quality (Table 1). The study
populations comprised strictly euthyroid subjects (26,29,30,
34,39,45,48,52–55,62,69,81,82,86,90,91), subjects either eu-
thyroid or with subclinical thyroid dysfunction (19,33,35,36,
38,40,42,47,49,60,65,71,73,75–78,80,92,93,95,96,98,99), and
subjects euthyroid or with subclinical/overt thyroid dys-
function (28,31,37,41,43,44,46,47,56,61,63,64,66,74,79,94).
In some studies, different subsets were examined separately.
The 58 articles included in our meta-analysis yielded 1880
results of associations analysis. The supplement catalogues all
of these associations in terms of clinical parameters, subgroups,
number of participants, statistical methods, statistical signifi-
cance, and p-values/confidence limits.
The number of subjects for each analysis ranged from 18
to 10,990 with a mean of 3071 (median 2078). The number
of results in each study ranged from 3 (60) to 180 (92).
Analysis of all these data confirmed the superiority of asso-
ciations with thyroid hormone levels (fT4, TT3/fT3) as com-
pared with TSH levels (Fig. 2). fT4 had a significant association
with a clinical parameter in 50% of the analyses of the articles.
TT3/fT3 had a significant association in 53% of the analyses,
whereas TSH had a significant association in only 23%. fT4
levels were associated with clinical parameters and were sta-
tistically significantly more often than with TSH levels,
(p < 0.0001), as did TT3/fT3, (p < 0.0001). The difference be-
tween fT4 and TT3/fT3 levels was not significant ( p = 0.71).
1698
FIG. 1. Description of
literature search.
When there was a significant association with fT4,
the association with TSH was simultaneously significant
30% of the time; for the converse, the frequency was 66%. For
TT3/fT3, the respective figures were similar at 33% and 62%.
The McNemar analysis demonstrated these results to be sig-
nificant; for the comparisons of fT4 versus TSH and TT3/
fT3 versus TSH, the null hypothesis was rejected (p < 0.0001).
For the comparison of fT4 versus TT3/fT3, we failed to reject
the null hypothesis (p < 0.4305).
As the number of subjects in the analysis increased, the su-
perior associations with thyroid hormones did not diminish
(Fig. 3), and similarly the system did not play a significant role
(Fig. 4). In an analysis including the number of covariates in the
original result, at higher numbers of covariates, the association of
clinical parameters with TT3/fT3 levels was no longer signifi-
cantly different from the association with TSH levels (Fig. 5).
The basic analysis provided earlier ignores the many sources
of dependence between the results reported in each study. To
account for this, it was necessary to incorporate a random in-
tercept for study in the model ( p = 2.2 · 10-16). There was still
then a statistically significant effect of thyroid test in predicting
FITZGERALD ET AL.
the significance of results ( p < 2.2 · 10-16). Post hoc pairwise
comparisons show that there was a statistically higher pro-
portion of significant results for fT4 compared with TSH
( p < 1 · 10-5), and also a statistically higher proportion of sig-
nificant results for TT3/fT3 compared with TSH ( p < 1 · 10-5).
These results confirmed those illustrated in the earlier men-
tioned confidence interval plots. We found that the additional
main effects of system, cohort size, and number of covariates
again did not improve the predictive effect of the model, com-
pared with one with just a thyroid test (based on minimizing the
Bayesian Information Criterion). We found that a nested ran-
dom effects structure of cohort within study was a statistically
valid addition to the model, but it did not change the observed
effects of the thyroid test on what has been cited earlier.
We found, when addressing the issue of dependence of re-
sults, a statistically significant effect of thyroid test on the
proportion of statistically significant results. Pairwise compar-
isons revealed that the only significant results in all four models
were for fT4 having more significant associations than TSH
(Table 2). In this analysis, TT3/fT3 levels did not have more
associations with clinical parameters than levels of TSH.
 Table 1. Description and Quality Assessment of Included Studies
Study Parameter Cohort study Population N (% female) Age NOS
Gammage et al. (28) AF Cross-section U.K. community 5860 (51) 72 (65–98) 9/9
Cappola et al. (26) Multiple parameters Prospective U.S. community 2843 (56) 75 – 5 9/9
Heeringa et al. (29) AF Cross-section Netherlands community 1455 (59) 68 – 8 9/9
Chaker et al. (30) AF Prospective Netherlands community 9166 (57) 65 – 9.9 9/9
Chaker et al. (86) Sudden cardiac death Prospective Netherlands community age ‡45 years 10,318 (57) 65 – 10 9/9
Kannan et al. (31) Heart failure, cardiac Cross-section U.S. heart failure cohort 1365 (35) 56.6 – 14.5 9/9
outcomes
Peixoto de Miranda Coronary artery disease Cross-section Brazil civil servants 767 (49.3) 58 9/9
et al. (91)
Roef et al. (89) Heart physiology Cross-section Belgium community 2078 (49) M 46 (41–51) 9/9
F 45 (40–50)
van de Ven et al. (81) Mortality Prospective Netherlands community 5816 (53) 56 – 18 9/9
Inoue et al. (82) Mortality Prospective U.S. community 5257 (not stated) 46 – 17 8/9
Yeap et al. (80) Mortality Prospective Australian community men 3885 (0) 77 – 3 9/9
Chan et al. (40) Cancer Prospective Australian community 3649 (56) 51 – 15 8/9
Tosovic et al. (41) Cancer Prospective Sweden community, women born 17,035 (100) 56.6 – 7.1* 9/9
during 1932–1950
Khan et al. (42) Cancer Prospective Netherlands community 10,318 (57) 61 (57–68) 8/9
Kuijpens et al. (43) Breast cancer Cross-section Netherlands community 2775 (100) 47–54 8/9
and prospective
van den Beld et al. (78) Frailty Prospective + Netherlands community men 403 (0) 78 (73–94) 9/9

1699
cross-section age ‡73 years
Yeap et al. (76) Frailty Cross-section Australia community men 3943 (0) 75 – 4 8/9
Bano et al. (77) Frailty Prospective Netherlands community 9419 (57) 65 – 10 9/9
n = 9419; age 65 – 10; female 57%
Gussekloo et al. (79) Frailty Prospective Netherlands community; all age 85 558 (66) 85 8/9
Volpato et al. (69) Dementia Prospective U.S. community women age ‡65 years 464 (100) 77 – 0.6 8/9
de Jong et al. (71) Dementia Cross-section Netherlands community 489 (48) 73 – 8 9/9
Chaker et al. (74) Dementia Prospective Netherlands community 9446 (43.3) 64.9 9/9
Itterman et al. (75) Dementia Cross-section Germany community 2557 (55) 51 – 10* 9/9
Yeap et al. (73) Dementia Prospective Australia community men 3401 (0) 79.2 – 3.5* 8/9
Roef et al. (34) Osteoporosis Cross-section Belgian community, men age 25–45 years 677 (0) 34 – 6 9/9
van der Deure et al. (36) Osteoporosis Cross-section Netherlands community age ‡55 years 1151 (58) 69 – 8 9/9
Murphy et al. (35) Osteoporosis Cross-section European post-menopausal women 1278 (100) 68 – 7 7/9
van Rijn et al. (33) Osteoporosis Cross-section Netherlands post-menopausal women 1477 (100) 50 – 2 9/9
Lambrinoudaki et al. (39) Vertebral fracture Cross-section Greece menopause clinic 335 (100) 56 – 7.1* 9/9
Siru et al. (38) Hip fracture, bone turnover Prospective Australian community men 338 (0) 76.7 – 3.5 9/9
Waring et al. (37) Bone loss, fracture Prospective U.S. community men 1602 (0) 73.6 – 5.9* 9/9
Proces et al. (60) Obesity Cross-section Belgium hospital outpatients 125 (44) 57 (13–89) 7/9
Wolide et al. (61) Obesity
Makepeace et al. (53) Obesity/Met S Cross-section Australian community 1853 (47) 49 – 17 9/9
n = 1853; age 49 – 17; female 47%
Mehran et al. (47) Obesity/Met S Prospective Iran community 2393 (61) 38 – 13 9/9
(continued)
 Table 1. (Continued)
Study Parameter Cohort study Population N (% female) Age NOS
Shon et al. (52) Obesity/Met S Cross-section Korea women medical centre primary 1572 (100) 46 – 11 9/9
health screening
Roos et al. (48) Obesity/Met S Cross-section Netherlands community 1581 (46) 48 – 12 9/9
Jun et al. (55) Obesity/Met S Cross-section Korea medical centre attendees 6235 (42) 50 – 8 9/9
Xu et al. (45) Obesity/Met S Cross-section China community 878 (37) 72 – 4 9/9
Bano et al. (46) Obesity/Met S Prospective Netherlands community 9640 (57) 65 – 10 9/9
Ittermann et al. (44) Obesity/Met S Cross-section Germany community 3661 (48) M 51 – 16 9/9
F 48 – 16
Knudsen et al. (49) Obesity/Met S Cross section Denmark community 4082 18–65 9/9
(‘‘preponderance’’)
Oh et al. (56) Obesity/Met S Cross-section Korea community 4275 (50) 49 9/9
Garduño-Garcia et al. (49) Obesity/Met S Cross-section Mexico community 3033 (51) 42 – 10 9/9
Temizkan et al. (62) Met S Cross-section Turkey obesity clinic 1275 (83) 38 – 11 9/9
Jain et al. (63) Lipids Cross-section U.S. population 3862 (not stated) Not stated 9/9

1700
Boekholdt et al. (64) Met S Cross-section U.K. community 11,554 (54) 58 – 9 9/9
Udenze et al. (65) Met S Cross-section Nigeria university staff 150 (54) 46.3 – 8.1 8/9
Elgazar et al. (66) Diabetes Cross-section Egypt hospital outpatients 400 (61) 54 – 4.9* 7/9
Chaker et al. (54) Diabetes Prospective Netherlands community 8542 (58) 65 – 10 9/9
Vrijkotte et al. (92) Foetal growth Prospective Netherlands community 3988 (100) 31 – 4.8 9/9
Korevar et al. (93) Premature delivery Prospective Netherlands community 5971 (100) 29.7 – 5.0 9/9
Medici et al. (94) Hypertensive pregnancy Prospective Netherlands community 5153 (100) 29.7 – 5.1 9/9
Cleary-Goldman et al. (95) Pregnancy outcome Prospective U.S. community 10,990 (100) 29.6 – 5.6 9/9
Breathnach et al. (96) Placental abruption Prospective Ireland community 904 (100) 26 – 6* 9/9
Ashoor et al. (97) Foetal death Retrospective England hospital 3794 (100) 32.2 (28–36) 8/9
Knight et al. (98) Pregnancy-metabolic Cross-section England community 741 (100) 30.1 – 5.1 9/9
parameters
Li et al. (99) Pregnancy-childhood Prospective China clinic 1268 (100) 28 – 2 9/9
development
*Age of largest subset of population.
F, female; M, male; Met S, metabolic syndrome; NOS, adapted Newcastle–Ottawa quality assessment scale (the higher number out of 9, the better the study).
ASSOCIATION OF THYROID TESTS AND CLINICAL STATES
The results of our sensitivity analysis aimed at minimizing
any effect of reverse causation showed no significant change
in the proportion of fT4 and TSH levels being associated
with clinical parameters, and hence in the statistical conclu-
sions. However, the association of TT3/fT3 levels with
clinical parameters was not significantly different than with
1701
FIG. 2. Overall associations of thyroid
hormone and TSH levels with clinical
parameters. T3, triiodothyronine; T4,
thyroxine; TSH, thyrotropin.
TSH levels. The proportion of associations with TT3/fT3 was
only 13% in this analysis as compared with 53% in the full
analysis.
There was no significant change to any of our results re-
garding the TT3/fT3 combination with consideration of
TT3 and fT3 separately.
FIG. 3. Associations of thyroid hormone
and TSH levels with clinical parameters
according to sample size.
1702 FITZGERALD ET AL.

FIG. 4. Associations of thyroid hormone

and TSH levels with clinical parameters
according to clinical system.

Only a few of the studies included patients on T4 therapy. Discussion

In these studies, the proportion of patients on T4 was very low
such that separate analyses of these patients were not un- We believe this is the first systematic review studying TSH
dertaken. Analyses of cohorts with removal of these patients and thyroid hormone associations with various clinical pa-
did not affect the results. rameters. The results indicate that, contrary to the current

FIG. 5. Associations of thyroid hormone

and TSH levels with clinical parameters
according to number of covariates.
ASSOCIATION OF THYROID TESTS AND CLINICAL STATES
Table 2. Model Description
Thyroid test fT4 vs. TSH
Smallest number p = 0.0001891 p = 0.000191
of subjects,
simple model
Smallest number p = 0.000773 p = 0.000658
of subjects,
complex model
Largest number p = 0.01126 p = 0.00931
of subjects,
simple model
Largest number p = 0.0006587 p = 0.000696
of subjects,
complex model
fT4, free thyroxine; TSH, thyrotropin.
paradigm, thyroid hormone levels are associated more
strongly with clinical parameters than TSH levels. Any re-
lationship of clinical parameters with TSH levels can be
explained by the strong population relationship between
thyroid hormone levels and TSH levels, such that TSH levels
are merely indirect measures of thyroid hormone levels.
In our sample, we found no indication of, or reference to,
any work that suggested that TSH levels consistently indicate
thyroid status of any organ or tissue more strongly than
thyroid hormone levels.
As our goal was not to estimate the effect size for one
treatment, our meta-analysis methodology differed from
some other meta-analysis methodologies in that we did not
use a weighted technique or pool all original patient data. In
addition, it would not have been appropriate to combine all
of these factors by using such meta-analysis methodology, as
our analysis encompassed multiple studies covering various
clinical outcomes, using different methodologies, different
assays, and statistical methods.
Theoretically, one could use such other methodology to do
a meta-analysis of each clinical parameter, but these indi-
vidual meta-analyses would still need to be combined by
using a method akin to ours (i.e., summing the meta-analyses
in some way) to determine whether levels of thyroid hor-
mones or TSH are more likely to be associated in general with
clinical parameters. Further, in using such a technique of
analysis, the information from many of the studies in our
sample would be lost as the parameter/population/statistical
method might not be amenable to pooling (27).
The results of the individual patient meta-analysis of AF
(27) do, in fact, support our conclusions, showing superior
associations with fT4 levels than with TSH levels. Also sup-
portive is a recently published similar meta-analysis of pre-
term delivery (100), showing that fT4 levels are associated
with the clinical parameter at least as well as TSH levels. One
could even argue that the results of these two conventional
meta-analyses alone disprove the general hypothesis that TSH
levels provide a better guide to thyroid status than fT4 levels.
Potentially, the summation of statistically significant results
can be unreliable (20], but we have accounted for the possi-
bilities of bias on account of imbalance in the size of the studies,
the nature of the parameters, and the possibility of reverse
causation. In all of the studies (except for the few studies
comparing individuals with subclinical hypothyroidism with
individuals with isolated hypothyroxinemia), each subject was
1703
his/her own control, and the study populations of many of the
studies were unselected members of a community, so the risk of
bias from these considerations was obviated. The convincing
degree of superiority of thyroid hormone levels as compared
with TSH levels also provides a buffer against the possibility of
some unidentified bias influencing our results.
The strictest interpretation of our data would, nevertheless,
qualify our conclusions such that they would be valid only to
the degree that the chosen parameters truly reflect the thyroid
state. Residual confounding, by mechanisms as yet incom-
pletely understood, may have affected the reported associa-
tions between thyroid function tests and all of the clinical
parameters. This possibility, not considered to be likely in the
studies we reviewed, would also compromise the previous
literature describing the considered consequences of sub-
clinical thyroid dysfunction.
However, even in these circumstances, a slightly weaker
conclusion for our study—that is, that there is no evidence
supporting the superiority of TSH levels in the assessment of
thyroid function—would still stand. Further, there is much
evidence to indicate that at least some of the chosen param-
eters do truly reflect the thyroid state.
In particular, although there are clinical parameters that
can affect thyroid function, we do not believe that such re-
verse causation significantly influence our results. Reverse
causation mechanisms have been described for parameters
associated with low thyroid function (e.g., obesity (101–103)
and dyslipidemia (57,58,104)), but in these circumstances the
reverse causation effects would tend to lead to greater asso-
ciations with TSH levels rather than with fT4 levels.
The sensitivity of TT3/fT3 levels to the sick euthyroid state
(105), generated by altered deiodinase activity (106), may
also explain some of the associations with TT3/fT3. In par-
ticular, mortality and frailty may be associated with low TT3/
fT3 levels via reverse causation. As the TSH would also be
expected to be low in this situation, one might expect in-
congruent associations between clinical parameters, and
TT3/fT3 (and possibly fT4) and TSH. Our sensitivity study
excluded such studies.
We are not aware of any association of a clinical parameter
with a high fT4 having been linked to reverse causation. If
anything, any component of the sick euthyroid state associ-
ated with these conditions, by lowering TSH and fT4 (105),
should again favor an association with TSH rather than fT4.
Mendelian randomization studies have provided evidence
that the relationship between thyroid function and AF is causal
(107,108), whereas there may be reverse causation underlying
the relationship between thyroid function and obesity (109).
Other indicators supporting a causative relationship between
thyroid function and at least some of the parameters we ex-
amined include the relationships being seen in otherwise
healthy individuals (91–99), the prospective nature of many of
our included studies, our sensitivity study, the observed simi-
larity of the relationships to those seen in overt thyroid disease
(110–120), basic science evidence (121,122), and positive
animal (123) and human (19) intervention studies.
Nevertheless, additional intervention studies could provide
further evidence as to the direction of causality in the asso-
ciations we have studied. Ideally, such intervention studies
would be designed to ensure that the intervention, rather than
merely normalizing TSH levels, significantly changes the
levels of thyroid hormones.
1704
We found TT3/fT3 level associations with fewer param-
eters than we found for fT4. Although TT3/fT3 levels were
associated more strongly than TSH levels, and equally
strongly as fT4 levels, with clinical parameters, our sensi-
tivity study showed a fall in the frequency of TT3/fT3 as-
sociations, suggesting a component of reverse causation.
Two other analyses, the analysis of associations according
to the number of covariates and the sampling analysis, also
indicated that the associations of clinical parameters with
TT3/fT3 may not be as robust as the associations with fT4
levels. Overall, TT3/fT3 measurement added little to the
assessment based on fT4 levels. Future studies may further
clarify the relative importance of fT4 and fT3 levels.
fT4 is not the active thyroid hormone at the cellular nuclear
level (106). The strong relationships of parameters, espe-
cially AF (risk increased up to 9 · across the normal reference
range (30)), with levels of fT4 indicate that the active intra-
cellular triiodothyronine generated by thyroid hormone
transporters and deiodinases (106) appears to be, at least in
the heart, proportional to circulating fT4. Any discrepancy,
indicating local regulation of thyroid effect, may be more
prominent in more severe pathophysiological circumstances
(106), and therefore more relevant in the circumstances of
multisystem entities such as frailty, death, and metabolic
disturbance.
Our results do not imply that no information can be
gleaned from the presence of an abnormal TSH level. In the
presence of normal thyroid hormone levels, such TSH levels
indicate that the thyroid gland physiology is abnormal.
However, for the function of other tissues and organs, the
TSH level required to maintain a given level of thyroid
hormones appears generally not to be relevant.
It remains possible too that additional analyses might find
that TSH levels are providing an additional signal to fT4
levels, in some populations for some conditions. It has been
suggested that TSH itself may have physiological effects
apart from the stimulation of thyroid hormone levels
(36,124), and such effects rather than via the reflection of
thyroid status might explain such a TSH signal. Empirically,
thus far, the evidence suggests that any of these TSH effects
are small.
The association of thyroid hormone and particularly fT4
levels, rather than TSH levels, with clinical features has been
noted by many authors, covering many individual parameters
(26–28,30,33,35,42,44,46–48,52,53,57,69,73,76,80,81,86).
In particular, the meta-analysis regarding AF noted the as-
sociation with fT4 but not with TSH (27). Authors also pre-
viously found evidence of associations of clinical parameters
with fT4 in the absence of an association with subclinical
thyroid dysfunction as currently diagnosed (33,49,73,80,86).
One of these studies also showed associations with TSH (49).
Nevertheless, to date, to the best of our knowledge, this
information from the individual studies showing the superi-
ority of thyroid hormone levels in terms of associations with
individual clinical parameters has not been synthesized into a
formal conclusion regarding the biochemical assessment of
thyroid function in general.
It has been suggested that despite TSH being considered
a more sensitive indicator of thyroid status, fT4 may be a
more sensitive indicator of ‘‘cardiac’’ (28), or ‘‘tissue’’
(47,53) thyroid status. Our study strengthens and generalizes
these propositions, indicating that fT4 is the more sensitive
FITZGERALD ET AL.
indicator of thyroid status because it is the better indicator of
tissue and organ effects.
The superior association of clinical parameters with fT4
as compared with TSH levels has more often been attributed
to a putative disturbance of set point physiology (42,46,47,
69,76,81,86), to a significant difference between pituitary and
peripheral sensitivity to fT4 (27,46,48,52), or to statistical/
other factors (including reverse causation) (33,36,44,49,58).
The explanations related to set points are denied in the first
instance by the evidence that the relatively stable thyroid
hormone levels seen in individuals are better explained by a
model of ‘‘balance points’’ (or ‘‘equilibrium points’’) rather
than ‘‘set points’’ (125). Notwithstanding this concept, it has
been suggested that in older adults there is an alteration of
what is termed ‘‘set point physiology,’’ in that TSH may be
less suppressed by any given rise in fT4 (42,76). However, in
this situation, though the range of TSH may change, any
physiological association with greater or lesser TSH levels
should remain intact. Further, the greater association of clin-
ical parameters with fT4 rather than TSH levels is apparent
across a wide age range (Table 1).
At a population level, TSH levels do, indeed, decrease with
rising fT4 levels (17,18), suggesting that in general pituitary
sensitivity to thyroid hormones is robust. If for any reason
there were a disturbance to pituitary sensitivity in the absence
of a corresponding change to peripheral sensitivity, this
would in any event provide another reason not to diagnose
thyroid function on the basis of TSH levels.
The evidence also suggests that, regardless of the method
used, the classification of thyroid function into normal, sub-
clinical disease and overt disease is arbitrary. Thyroid hor-
mones, as previously suggested (9,26), similar to many other
biological parameters, exert a continuum of effects across the
normal range. There is no clear border between normal and
abnormal. There are advantages and disadvantages associ-
ated with all levels (9,26,126). Individuals with relatively low
levels of fT4, for example, are less likely to develop AF but
more likely to develop metabolic syndrome; the converse
applies for individuals with higher fT4 levels. At the ex-
tremes, the disadvantages clearly outweigh the advantages,
and individuals are likely to become symptomatic.
On the other hand, any excursion from the middle of the
range has an association with some pathology or other. Some
individual pathologies, for example, frailty, mortality, and
dementia may increase with deviations either side of the
middle of the range. It seems likely that evolutionary mech-
anisms have arisen to minimize variation from the middle of
the reference range of thyroid hormones (127).
The fact that TSH levels reliably identify overt thyroid
dysfunction can also be explained by the negative population
relationship between TSH and fT4, that is, its extension into
the abnormal ranges of fT4 (17,18). This extension is due
merely to the fact that the vast majority of all overt thyroid
dysfunction is primary rather than secondary (128). This
situation differs from other endocrine pathology, for example
Cushing’s syndrome, where ACTH levels cannot be used as a
screening test on account of the likelihood that Cushing’s
syndrome may be secondary, that is, be due to a disorder of
ACTH regulation (129). The fact that TSH levels are thereby
very sensitive screening tests for overt thyroid dysfunction
(130) does not imply that TSH levels are very specific, that
is, that an abnormal TSH level implies thyroid dysfunction.
ASSOCIATION OF THYROID TESTS AND CLINICAL STATES
Our work indicates that an abnormal TSH level per se is an
imprecise indicator of tissue or organ hyper/hypothyroidism
as compared with thyroid hormone levels.
This work addressed diagnosis alone. Extrapolation of our
findings appears logical, and there is no apparent a priori
reason as to why TSH levels should be preferred over thyroid
hormone levels in the context of monitoring thyroid treat-
ments. Randomized trials might, nevertheless, reveal that
additional considerations apply in these circumstances.
Though there was no suggestion in the studies that we ex-
amined of a difference with individuals on thyroid hormone
replacement, their numbers were small.
In summary, there is now matching theoretical and empiric
evidence from a variety of sources suggesting that the thyroid
status of an individual is better defined by thyroid hormone
levels than TSH levels. There is evidence of a continuum of
thyroid hormone effects along the continuum of thyroid
hormone levels, with a possible optimum around the middle
of the reference range. Though TSH levels remain good
screening tests for overt thyroid dysfunction, it is theoreti-
cally and empirically more sound to rely on thyroid hormone
and especially fT4 levels to classify the thyroid state.
This work should result in a simplification of the under-
standing of thyroid physiology and pathophysiology, and
bring it more into line with the understanding of the physi-
ology and pathophysiology of other parameters, whereby the
status of a parameter is judged by its level rather than the
level of any controlling factor. Reconsideration of the TSH-
based diagnostic approach to thyroid function appears to be
indicated. In turn, this would appear to have implications for
clinical guidelines, research methodology, and the rationale
of underlying physiological principles.
Author Disclosure Statement
No competing financial interests exist.
Funding Information
No funding was received for this article.
Supplementary Material
Supplementary Table S1
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Address correspondence to:
Stephen P. Fitzgerald, MBBS, FRACP
Department of General Medicine
Royal Adelaide Hospital
Port Road
Adelaide 5000
South Australia
E-mail: stephen.fitzgerald2@sa.gov.au